Uterine Hemostasis Colloquium

The Challenges of Obstetric and Gynecologic Bleeding in the Reproductive Years

Preceding HTRS 2017 10th Scientific Symposium

Program Co-Chairs:

Andra H. James, MD, MPH and Kenneth G. Mann, PhD

Program Description:

The proposed meeting, a national colloquium on uterine hemostasis, will convene leading faculty/researchers/clinicians to review our current understanding of the science as well as current evidence-based practice related to the diagnosis and clinical management of abnormal uterine hemostasis. It will examine current understanding and practice as applied to:

acute abnormal bleeding

postpartum hemorrhage

underlying bleeding disorders

Long-term impact: To improve the recognition of the role of uterine hemostasis in abnormal uterine bleeding, in postpartum hemorrhage and among women with bleeding disorders

Normal Uterine Anatomy and Histology of the Non-Pregnant and Pregnant Uterus

Evelyn Lockhart, MD

Abstract:

Hemostasis results from the interaction between the cellular elements of blood, plasma proteins, and damaged tissue. Regional tissue bed variations can impact hemostasis, so considerations of uterine hemostasis benefit from the review of uterine anatomy and histology. The uterus is one of the most dynamic organs in the body, undergoing changes throughout a woman’s lifecycle, but also undergoing profound change during gestation. In this talk, we will review the anatomy of the uterus and its relationship to other pelvic organs. The histology of the endometrium and myometrium will be emphasized, focusing on the cyclical changes throughout the menstrual cycle as well as through pregnancy. Lastly, we will review the vascular supply to the uterus. At term gestation, the gravid uterus receives more than 500 mL of blood flow per minute; the anatomic changes of the gravid uterus will be correlated with the vascular supply alterations during pregnancy.

Menstrual cycle hormonal changes occur with estradiol concentrations lowest during menses and highest on days 13-15 and progesterone lowest on days 1-8 and highest on days 21-25. Cyclical variation in hemostasis has been found during the menstrual cycle for some hemostatic parameters, but not for others. Von Willebrand factor levels have been found to be lower during menstruation and the early follicular phase compared to the luteal phase. Although there is limited data on platelet function, closure times on the PFA100 using the collagen/epinephrine cartridge have been shown to be shorter during the luteal phase, compared to the follicular phase. However, the effects of the menstrual cycle on platelet aggregation are not known. Cyclic variation has been observed for some coagulation factors and not others. Factor VII has been reported to be significantly lower during the luteal phase than during the follicular phase, and factor XIII lowest peri-ovulatory. No significant cyclic variation has been shown for factors II, X, and XI. Cyclic variation in fibrinogen has been shown, with most studies demonstrating the lowest levels during the follicular phase. Some studies have shown cyclic variation with plasma fibrinolytic parameters, however, there is inconsistency in whether fibrinolytic parameters are lowest during the follicular or luteal phase. In women, cycle specific hemostatic testing may be considered for hemostatic parameters shown to have cyclic variation especially when borderline results are obtained. The impact of cyclic variation of plasma hemostatic parameters on bleeding and thrombotic risks is unknown.

Section 2: Uterine Hemostasis Postpartum: with an Introduction to the Magnitude of the Problem of Obstetric HemorrhageModerated by Mike Foley, MD and Barbara A. Konkle, MD

Obstetric hemorrhage is a leading cause of serious maternal morbidity and maternal mortality in the United States. Uterine atony is the most common cause, but abnormalities of placentation, including placental abruption, placenta previa, and placenta accreta, are also major contributors. Abruption, bleeding at the decidual-placental interface, may be due to trauma or vasoconstrictive agents but most often occurs in association with chronic placental disease that increases the likelihood of maternal vascular disruption in the decidua basalis. Severe abruption is associated with rapidly-developing hyperfibrinogenemia and DIC. Placenta previa refers to the presence of placental tissue implanted in the lower uterine segment that covers the internal cervical os. A majority of patients with placenta previa will have antepartum bleeding in the second half of pregnancy, usually after 28 weeks’ gestation, though it is difficult to predict the severity. Placenta previa poses an increased risk of postpartum hemorrhage due to the implantation being in the less contractile lower uterine segment. The most common predisposition to placenta previa is prior cesarean section. And the combination of a prior cesarean and a placenta previa greatly increases the likelihood of placenta accreta, a condition of morbidly adherent placenta secondary to the implantation being in the myometrium rather than the decidua. The morbid adherence is thought to be due to a failure of normal decidua basalis to form within the site of prior endometrial scarring. Placenta accreta was infrequent prior to the 1980s but is now estimated to complicate about 1 in 1000-2500 deliveries in the U.S., an increase directly related to the increasing population of women with prior cesarean section. The most serious cases of placenta accreta involve trophoblast invasion into tissues beyond the myometrium (placenta percreta), such as the bladder and broad ligament. Even in the most experienced hands, the surgical management of placenta accreta is sometimes complicated by urinary tract injury and the need for blood product replacement exceeding 10 units; the maternal mortality rate due to massive hemorrhage may be as high as 0.5%.

Early in pregnancy, uterine spiral arterioles that provide the blood supply to the endometrium are converted to uteroplacental arteries, which become largely unresponsive to vasoconstrictive agents. After delivery and with separation of the placenta from the uterine wall, as the blood vessels supplying the placental bed are unable to constrict, the uterus must contract in a tonic fashion to allow the uteroplacental arteries to close and further bleeding. Thus, adequate uterine contractility is necessary to prevent postpartum hemorrhage. Uterine contractions occurring during and immediately following delivery, are largely driven by oxytocin, which exerts its action through the oxytocin receptor (OXTR). The OXTR is a G protein-coupled receptor and is prone to molecular desensitization. Prolonged exposure to and high dosing of oxytocin during labor increase the risk for OXTR desensitization. Desensitization of the OXTR manifests clinically as decreases in uterine contractility which may present as uterine atony and postpartum hemorrhage. Furthermore, preliminary data suggest that there is also genetic variation in single nucleotide polymorphisms in the OXTR and GRK6 (regulates OXTR desensitization) genes that are associated with oxytocin dosing requirements in labor. Genetic as well as environmental factors, together or individually, may influence the degree of uterine contractility following delivery, thereby affecting a woman’s risk of postpartum hemorrhage.

In this presentation, we will review the evidence that uterine hemostasis at the time of parturition appears to be achieved, at least partly, by thrombosis of uterine veins. No matter how advanced the gestation, at the conclusion of pregnancy, the placenta should separate from the wall of the uterus and be expelled. Separation of the placenta exposes the open spiral arteries (the terminal branches of the uterine arteries) and the uterine veins, resulting in bleeding across the uterine surface previously occupied by the placenta. The mechanism by which bleeding from these vessels is controlled is initially contraction of the uterus. Other factors, not well understood, lead to vasoconstriction of the spiral arteries. There is microscopic evidence that the spiral arteries are subsequently obliterated and the uterine veins thrombose. Recently, there is macroscopic evidence that not only the uterine veins but the pelvic veins thrombose as well, at least partially. There is confirmatory evidence at the biochemical level. It appears that fibrinogen, factor VIII, and antithrombin are consumed at the time of delivery.

Normal menstrual blood flow is a monthly coordinated program of tissue autodigestion triggered by hormonal changes. Platelets and coagulation factors play a vital role in regulating bleeding during normal menstrual blood flow. Morphologic studies of normal uterine tissue demonstrate the presence of platelet plugs and degranulated platelets within hours of the initiation of menstruation and layers of platelet plugs and fibrin clots in vessel lumen as menstruation progresses. Subtle cyclic changes in platelet counts throughout the ovarian cycle and presence of estrogen receptors on platelets indicate a more directed role for platelets in uterine physiology. The high incidence of bleeding disorders, particularly von Willebrand disease and disorders of platelet function, in women with heavy menstrual bleeding provides further evidence that normal platelet function is essential for regulating menstrual blood loss. This session will review the contribution of platelets to normal menstrual hemostasis through review of histologic studies, discussion of hormonal effects on platelet number and function, and evaluation of patients presenting with heavy menstrual bleeding.

My defense of the proposition that uterine hemostasis is achieved when there is normal coagulation factor function is based on two lines of evidence: 1) subjects with inherited disorders of coagulation experience excessive (sometimes fatal) uterine bleeding related to menstruation and pregnancy; and 2) mother nature has apparently found it beneficial to equip women with increased levels of certain coagulation factors in the plasma, and inhibitors of fibrinolysis in the placenta as parturition approaches. A coagulation factor deficiency is not the most common cause of excessive menstrual or peripartum bleeding. However, an increased risk of reproductive tract bleeding has been associated with these conditions. von Willebrand Disease (VWD) is the most common inherited bleeding disorder in women, therefore the risk of bleeding is best described in VWD. The first patient described with this disorder notably bled to death during her fourth menstrual period. The prevalence of menorrhagia in women with VWD is reported to be 74-92%, and the prevalence of VWD in women with menorrhagia has been reported to be about 13%. A number of case series also document the increased risk of post-partum hemorrhage in VWD, which is characteristically delayed after delivery. While many fewer patients have been studied, registry data suggest that women with rare bleeding disorders are at greater risk of menorrhagia. Conversely, the progressive development of a prothrombotic state as pregnancy approaches term, suggests that enhanced hemostatic function in the peripartum period has survival value for mother and child.

Day 2: Thursday, April 6, 2017

Section 4: What are the existing management options and what are the clinical research opportunities? Moderated by Michael Paidas, MD, and Catherine Peterson-Layne, MD

Lessons From Trauma Surgery

Mitchell J. Cohen, MD

VIEW PDF of SLIDES

Abstract:

Trauma remains the leading cause of death and disability in patients less than 54 years old, eclipsing ischemic heart disease, stroke and HIV/AIDS. Control of hemorrhage is the therapeutic cornerstone of in severely injured trauma victims. Translational work by many groups have resulted in a recognition there is an acute traumatic coagulopathy which is an endogenous biological response occurring immediately after injury which is associated with increased bleeding, transfusion and resuscitation requirements and results in early death and (in victims who survive) later inflammatory and infectious complications. This ATC is independent and separate from iatrogenic coagulopathy which occurs secondary to resuscitation practices which cause or allow hypothermia, dilution, and acidosis. Translational data suggests that the severity of injury and tissue hypoperfusion are contributing factors to the development of ATC which mechanistically occurs as a result of activation of the protein C pathway causing impaired coagulation and derepression of fibrinolysis. Significant additional work has ensued to identify drivers of impaired coagulation and bleeding after injury and to tailor resuscitative practices to prevent bleeding and save lives. While inspired by traumatic injury much of this work is germane to other cause of bleeding including obstetric hemorrhage. Hence this talk will discuss lessons which can be learned about the basic mechanisms, clinical phenotypes and targeted resuscitation and treatment from trauma with the hope that these can be applied to the critical topic of obstetric hemorrhage.

Heavy menstrual bleeding (HMB) may manifest around menarche or even later in life. In reproductive age women, evaluation of HMB involves assessment of anatomic (uterine) and systemic factors (including the possibility of an underlying bleeding disorder). HMB may manifest over several months or present as acute uterine hemorrhage. Gynecologic care for these women, therefore, spans decades and impacts decisions for menstrual management and contraception. A review of strategies and options for managing menses, contraception and acute bleeding episodes will be presented.

Since heavy menstrual bleeding (HMB) is characterized by increased fibrinolysis of the menstrual fluid, tranexamic acid (TA) has been a mainstay of treatment for decades for the general HMB population. Since 2009, a sustained release formulation of TA available in the United States (U.S.) termed LYSTEDATM has been approved for the general HMB population dosed at two tablets of 650 mg/tablet three times a day for the first five days of menses. Menstrual blood flow (MBL) was reduced 41% compared to 8% in the placebo arm accompanied by significant improvements in numerous quality of life (QOL) parameters. On-going issues regarding TA use presently include whether it’s as effective and as tolerated as well in the adolescent population and whether it can be used safely concurrently with estrogen-based contraception. Since HMB is invariably seen in patients with an underlying disorder of hemostasis like von Willebrand Disease (VWD), another potential treatment for HMB is desmopressin (DDAVP) that predictably elevates VWF levels and reduces menstrual flow in women with VWD-related HMB. A relatively large multi-center U.S. crossover trial of women with abnormal laboratory hemostasis (including VWD) comparing IN (intranasal)-DDAVP and TA using the PBAC for assessment of MBL and four previously validated QOL measures was carried out. Both medications reduced menstrual flow and improved QOL among females with HMB and abnormal laboratory hemostasis, but TA proved to be more effective than IN-DDAVP. In further improving the efficacy of these hemostatic agents for HMB, the study of the efficacy and safety of combined therapy of IN DDAVP and anti-fibrinolytic therapy or also hormonal therapy is in order.

The treatment of postpartum hemorrhage is largely directed at inducing tonic uterine contractions following delivery of the placenta, allowing for the closure of uteroplacental arteries that provides blood supply to the placental bed. Continuous intravenous infusion of oxytocin following delivery of the placenta remains the mainstay for prevention of postpartum hemorrhage. Boluses of oxytocin help transform the uterus from a phasic contractile pattern that is seen during labor, to one of a tonic contractile pattern characteristic of the postpartum state. Uterine atony, or failure of the uterus to adequately contract following delivery, is the most common etiology of postpartum hemorrhage. Prolonged exposure to oxytocin or the use of high-dose oxytocin infusions, prolonged labor, chorioamnionitis, and over-distension of the uterus are all associated with an increased risk for uterine atony. Once uterine atony is diagnosed, continued infusion of oxytocin remains the first line-agent. With persistent uterine atony and associated uterine bleeding, other uterotonic medications that enhance uterine contractility are employed. These agents induce smooth muscle contraction and include prostaglandins (carboprot [prostaglandin F2a] or misoprostol [prostaglandin E1]) and the ergots (methylergometrine). If repeated dosing of these various agents does not induce adequate uterine contraction responses, surgical methods that occlude the uterine cavity are next utilized. Uterine packing or the use of external uterine compression sutures allow for occlusion of the uterine cavity, attempting to limit uterine bleeding. Finally, decreasing perfusion to the uterus either with uterine artery embolization or uterine artery ligation/sequential uterine devascularization are next employed. Finally, hysterectomy remains the final and definitive therapy for postpartum hemorrhage that is otherwise unresponsive to medical therapy and other surgical therapy.

Obstetric hemorrhage remains a leading cause of maternal morbidity and mortality worldwide. While most obstetric hemorrhages will respond to obstetric or surgical management, some may be complicated by coagulopathy requiring hematologic management. Coagulopathy in obstetric hemorrhage merits distinct consideration from the coagulopathy seen in trauma or other perioperative settings due to the physiologic changes in hemostatic systems observed during pregnancy. This presentation will review laboratory monitoring of obstetric hemorrhage, including, 1) fibrinogen as a predictor of severe postpartum hemorrhage, and 2) viscoelastic clot-based testing (thromboelastometry) as predictors of severe postpartum hemorrhage. In addition, we will review data regarding fibrinogen repletion in postpartum hemorrhage. Lastly, we will review the data on use of antifibrinolytic agents such as tranexamic acid in the setting of postpartum hemorrhage